Of all the salts of S (−) Amlodipine mentioned above, S (−) Amlodipine besylate (4-S)-2-{[(2-aminoethyl)oxy]methyl}-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate benzene sulfonate has commercial importance as a potent long acting calcium channel blocker.
R(+) Amlodipine has been reported as a potent inhibitor of smooth muscle cell migration (PCT/EP-94/02697). (R, S) amlodipine and its salts are long acting calcium channel blockers and are useful for the treatment of cardiovascular disorders. Racemic amlodipine is currently being used for the treatment of hypertension and angina as a besylate salt. The preparation of racemic compound is described in EP 0089167. Amlodipine is racemic compound and has chiral center at 4 position of dihydropyridine ring. The S(−) isomer is having calcium channel blocker activity while R(+) isomer is a potent inhibitor of smooth muscle cell migration. Prior arts herein for the preparation of R and S enantiomers are a) resolution of amlodipine azide ester with optically active 2-methoxy-2-phenylethanol (J. Med. Chem. 29, 1696, 1986, EP appl. 0331315 A) or b) resolution of amlodipine base with optically active camphanic acid (J. Med. Chem. 35, 3341, 1992) c) resolution of R S amlodipine base with L (+) or D(−) tartaric acid respectively in organic solvent DMSO (USP 6,046,338 (2000) PCT95/25722 1995) d) resolution of penultimate azidoester precursor of amlodipine using cinchonidine. (USP 6,291, 490(2001), Chem. Pharm. Bull. 28 (9), 2809-2812, 1980).
Preparation of S(−) amlodipine besylate has been disclosed in the publication (J. Chem. B., 693, 1997, 367-375, followed by fully described and claimed in out co-pending patent application no. NF347/02 which relates to the process for the preparation of pharmaceutically acceptable salts of S(−) Amlodipine such as besylate, succinate, maleate, oxalate and tosylate from S(−) Amlodipine.
The main disadvantages of the prior art are:
    1. The use of costly resolving agents like camphanic acid, 2-methoxy-2-phenylethanol, cinchonidine.    2. The use of 0.5 mole of L (+) or D(−) tartaric acid increasing the load of recovery of tartaric acid.    3. Low yield of isolated resolved salt using less quantities of resolving agent.    4. Use of large volumes of solvent (1:10)    5. Isolation of free chiral base from the salt and treatment with benzene sulfonic acid to get besylate salt.